A fundamental characteristic of excessive alcohol use is the comorbidity of alcohol dependence and disorders of affect. Self-medication of these negative affective states likely contributes to excessive alcohol use and relapse. Negative affective states produced by chronic alcohol exposure result from neuroadaptations in motivational and affective neurocircuitry that are not yet understood. The principal investigator's long-term goal is to identify effective pharmacotherapeutic targets for the treatment of alcoholism. The objective of this application, which is the next step in pursuit of that goal, is to understand the neuroadaptations in dynorphin / kappa-opioid systems that occur in response to chronic alcohol exposure and contribute to attenuated motivational and affective states. The central hypothesis is that compensatory neuroadaptations in dynorphin / kappa-opioid systems oppose the acute effects of alcohol, and promote excessive alcohol intake by altering negative affective behaviors. The rationale for the proposed studies is that identification of dynorphin targets will enable the development of pharmacotherapies designed to alleviate motivational and affective symptoms produced by alcohol dependence. The hypothesis will be tested by pursuing the following specific aims:
Aim #1 will evaluate kappa opioid receptor antagonism within specific sites of the extended amygdala during acute withdrawal.
Aim #2 will site-specifically evaluate the role of extended amygdala dynorphin systems in depressive- and anxiety-like behavior.
Specific Aim #3 will maximize dependence-induced alterations in negative affective behaviors during acute and protracted withdrawal. All three aims will utilize animal models of ethanol reinforcement and affective behavior to allow for the systematic investigation of neurotransmitter systems and neurocircuitry that contribute to altered motivational and affective states produced by chronic ethanol exposure. These three specific aims will collectively help to identify important neuroadaptations that result from chronic alcohol exposure and provide much needed information regarding the neurocircuitry involved in altered motivational and affective systems. Such a contribution is significant because it will help to develop pharmacotherapeutic targets for the treatment of alcoholism that focus on the removal of attenuated motivational and negative affective states;a strategy that should greatly increase medication compliance and decrease rates of relapse.
This proposal is relevant to public health and will have an important positive impact because there are currently no pharmacotherapies designed to alleviate the negative affective and attenuated motivational aspects of alcohol withdrawal and dependence. In addition to the site-specific investigation of dynorphin / kappa-opioid systems in reinforcement paradigms, the benefits of this proposal are the assessment of dynorphin / kappa-opioid systems in depressive- and anxiety-like behaviors associated with alcohol dependence. The proposed experiments will assist with the development of pharmacological targets for alcoholism based on the alleviation of negative affect and result in increased compliance and treatment success for the individual and less alcoholism-associated societal costs.
|Sirohi, Sunil; Aldrich, Jane V; Walker, Brendan M (2016) Species differences in the effects of the ?-opioid receptor antagonist zyklophin. Alcohol 51:43-9|
|Kissler, Jessica L; Walker, Brendan M (2016) Dissociating Motivational From Physiological Withdrawal in Alcohol Dependence: Role of Central Amygdala ?-Opioid Receptors. Neuropsychopharmacology 41:560-7|
|Mann, Karl; Torup, Lars; Sørensen, Per et al. (2016) Nalmefene for the management of alcohol dependence: review on its pharmacology, mechanism of action and meta-analysis on its clinical efficacy. Eur Neuropsychopharmacol 26:1941-1949|
|Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda et al. (2015) Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area ? Opioid Receptors. J Neurosci 35:12217-31|
|Sirohi, Sunil; Walker, Brendan M (2015) Maturational alterations in constitutive activity of medial prefrontal cortex kappa-opioid receptors in Wistar rats. J Neurochem 135:659-65|
|Kissler, Jessica L; Sirohi, Sunil; Reis, Daniel J et al. (2014) The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors. Biol Psychiatry 75:774-82|
|Walker, Brendan M; Kissler, Jessica L (2013) Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats. Neuropsychopharmacology 38:2278-85|
|Berger, Anthony L; Williams, Angela M; McGinnis, Molly M et al. (2013) Affective cue-induced escalation of alcohol self-administration and increased 22-kHz ultrasonic vocalizations during alcohol withdrawal: role of kappa-opioid receptors. Neuropsychopharmacology 38:647-54|
|Walker, Brendan M; Valdez, Glenn R; McLaughlin, Jay P et al. (2012) Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence. Alcohol 46:359-70|
|Roberto, Marisa; Kash, Thomas L; Mulholland, Patrick J et al. (2012) Introduction to Young Investigator Award Symposium: Symposium XII: Young Investigator Award. Alcohol 46:301-2|
Showing the most recent 10 out of 15 publications